title: Mannosylated bioreducible nanoparticle-mediated macrophage-specific TNF-α RNA interference for IBD therapy.
abstract: The application of RNA interference (RNAi) for inﬂammatory bowel disease (IBD) therapy has been limited by the lack of non-cytotoxic, efficient and targetable small interfering RNA (siRNA) carriers. TNF-α is the major pro-inflammatory cytokine mainly secreted by macrophages during IBD. Here, a mannosylated bioreducible cationic polymer (PPM) was synthesized and further spontaneously assembled nanoparticles (NPs) assisted by sodium triphosphate (TPP). The TPP-PPM/siRNA NPs exhibited high uniformity (polydispersity index = 0.004), a small particle size (211-275 nm), excellent bioreducibility, and enhanced cellular uptake. Additionally, the generated NPs had negative cytotoxicity compared to control NPs fabricated by branched polyethylenimine (bPEI, 25 kDa) or Oligofectamine (OF) and siRNA. In vitro gene silencing experiments revealed that TPP-PPM/TNF-α siRNA NPs with a weight ratio of 40:1 showed the most efficient inhibition of the expression and secretion of TNF-α (approximately 69.9%, which was comparable to the 71.4% obtained using OF/siRNA NPs), and its RNAi efficiency was highly inhibited in the presence of mannose (20 mm). Finally, TPP-PPM/siRNA NPs showed potential therapeutic effects on colitis tissues, remarkably reducing TNF-α level. Collectively, these results suggest that non-toxic TPP-PPM/siRNA NPs can be exploited as efficient, macrophage-targeted carriers for IBD therapy.
authors.affiliation: Department of Biology and Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta 30302, USA. bxiao@gsu.edu
authors.forename: Bo
authors.initials: B
authors.lastname: Xiao
authors.forename: Hamed
authors.initials: H
authors.lastname: Laroui
authors.forename: Saravanan
authors.initials: S
authors.lastname: Ayyadurai
authors.forename: Emilie
authors.initials: E
authors.lastname: Viennois
authors.forename: Moiz A
authors.initials: MA
authors.lastname: Charania
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Zhang
authors.forename: Didier
authors.initials: D
authors.lastname: Merlin
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D016923:Cell Death / Q000187:drug effects; D004587:Electrophoresis, Agar Gel; D004705:Endocytosis / Q000187:drug effects; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000628:therapy*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008358:Mannose / Q000378:metabolism*; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D010316:Particle Size; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011122:Polyphosphates / Q000737:chemistry / Q000494:pharmacology; D034622:RNA Interference / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D017186:Titrimetry; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D011108:Polymers; D011122:Polyphosphates; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; C005692:triphosphoric acid; D008358:Mannose
keywords: Bioreducible polymer; IBD therapy; Macrophage-targeted delivery; Mannosylation; RNA interference